Project Summary (Abstract) Alzheimer's disease (AD) causes alterations in sensory systems ?such as olfaction or hearing-, and motor domains that sometimes precede cognitive symptoms, as shown in longitudinal studies. However, it remains largely unknown the specific role of sensory and motor disruptions within the AD neurodegeneration process and its clinical use for predicting future dementia onset. In this proposal, we focus on the network nature of sensory and motor changes in the aging brain. We postulate that AD neurodegeneration transversally affects connectivity streams across neuronal systems involving multiple domains of network integration, from sensory-motor to high-order cognitive brain centers. Thus, we will investigate the functional streams connecting sensory and motor regions with associative cortex to disentangle the role of sensory-motor disruption in the disease and its relationship with tau and amyloid accumulation at the brain circuit level. Particularly, we will use functional connectivity MRI, multimodal PET neuroimaging (tau and amyloid tracers), and graph theory metrics to reliably quantify the sensory and motor circuit changes in the cerebral tissue of preclinical and clinical AD samples from our local Harvard Aging Brain Study at Massachusetts General Hospital. Our preliminary data has demonstrated that network analysis can provide a highly accurate quantitative map of the sensory-motor systems connectivity in aging populations, offering a firm basis for assessment of AD related changes in brain function. In this multi-disciplinary investigation we will 1) quantify sensory and motor functional streams in aging and AD (Aim 1); 2) investigate the association of sensory and motor functional streams with tau and amyloid deposits (Aim 2); and 3) investigate the sensory and motor connectivity changes in the follow-up (Aim 3).